rs121918653

Positions:

• chr12-88545774-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000899.5(KITLG):​c.107A>G​(p.Asn36Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KITLG NM_000899.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.80

Genes affected

KITLG (HGNC:6343): (KIT ligand) This gene encodes the ligand of the tyrosine-kinase receptor encoded by the KIT locus. This ligand is a pleiotropic factor that acts in utero in germ cell and neural cell development, and hematopoiesis, all believed to reflect a role in cell migration. In adults, it functions pleiotropically, while mostly noted for its continued requirement in hematopoiesis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a disulfide_bond (size 85) in uniprot entity SCF_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000899.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-88545774-T-C is Pathogenic according to our data. Variant chr12-88545774-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12813.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-88545774-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KITLG	NM_000899.5	c.107A>G	p.Asn36Ser	missense_variant	2/10	ENST00000644744.1	NP_000890.1
KITLG	NM_003994.6	c.107A>G	p.Asn36Ser	missense_variant	2/9		NP_003985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KITLG	ENST00000644744.1	c.107A>G	p.Asn36Ser	missense_variant	2/10		NM_000899.5	ENSP00000495951	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperpigmentation with or without hypopigmentation, familial progressive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;T
Eigen	Benign	-0.0049
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	0.44	A;A
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.92	.;N;N
REVEL	Benign	0.13
Sift	Benign	0.093	.;T;T
Sift4G	Uncertain	0.030	.;D;D
Polyphen		0.012	B;B;B
Vest4		0.39, 0.34
MutPred		0.91		Loss of stability (P = 0.1187);Loss of stability (P = 0.1187);Loss of stability (P = 0.1187);
MVP		0.58
MPC		0.16
ClinPred		0.61	D
GERP RS		5.7
Varity_R		0.21
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918653; hg19: chr12-88939551;